tbuckley/cabot-search huggingface dataset:
Hypoxia-Responsive CAR-T Cells Exhibit Reduced Exhaustion and Enhanced Efficacy in Solid Tumors
Authors: Xiuxiu Zhu, Jun Chen, Wuling Li, Yanmin Xu, Juanjuan Shan, Juan Hong, Yongchun Zhao, Huailong Xu, Jiabin Ma, Junjie Shen, Cheng Qian
Journal: Cancer Research (2023)

Abstract Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors that could be used to help CAR-T cells discriminate tumors from normal tissues. In this study, we developed hypoxia-responsive CAR-T cells by engineering the CAR to be under regulation of hypoxia-responsive elements and selected the optimal structure (5H1P-CEA CAR), which can be activated in the tumor hypoxic microenvironment to induce CAR-T cells with high polyfunctionality. Hypoxia-responsive CAR T cells were in a “resting” state with low CAR expression under normoxic conditions. Compared with conventional CAR-T cells, hypoxia-responsive CAR-T cells maintained lower differentiation and displayed enhanced oxidative metabolism and proliferation during cultivation, and they sowed a capacity to alleviate the negative effects of hypoxia on T-cell proliferation and metabolism. Furthermore, 5H1P-CEA CAR-T cells exhibited decreased T-cell exhaustion and improved T-cell phenotype in vivo. In patient-derived xenograft models, hypoxia-responsive CAR-T cells induced more durable antitumor activity than their conventional counterparts. Overall, this study provides an approach to limit CAR expression to the hypoxic tumor microenvironment that could help to enhance CAR T-cell efficacy and safety in solid tumors. Significance: Engineering CAR-T cells to upregulate CAR expression under hypoxic conditions induces metabolic reprogramming, reduces differentiation, and increases proliferation to enhance their antitumor activity, providing a strategy to improve efficacy and safety.
Evaluation and Treatment of Knee Pain
Authors: Vicky Duong, Win Min Oo, Changhai Ding, Adam G. Culvenor, David J. Hunter
Journal: JAMA (2023)

Importance Approximately 5% of all primary care visits in adults are related to knee pain. Osteoarthritis (OA), patellofemoral pain, and meniscal tears are among the most common causes of knee pain. Observations Knee OA, affecting an estimated 654 million people worldwide, is the most likely diagnosis of knee pain in patients aged 45 years or older who present with activity-related knee joint pain with no or less than 30 minutes of morning stiffness (95% sensitivity; 69% specificity). Patellofemoral pain typically affects people younger than 40 years who are physically active and has a lifetime prevalence of approximately 25%. The presence of anterior knee pain during a squat is approximately 91% sensitive and 50% specific for patellofemoral pain. Meniscal tears affect an estimated 12% of the adult population and can occur following acute trauma (eg, twisting injury) in people younger than 40 years. Alternatively, a meniscal tear may be a degenerative condition present in patients with knee OA who are aged 40 years or older. The McMurray test, consisting of concurrent knee rotation (internal or external to test lateral or medial meniscus, respectively) and extension (61% sensitivity; 84% specificity), and joint line tenderness (83% sensitivity; 83% specificity) assist diagnosis of meniscal tears. Radiographic imaging of all patients with possible knee OA is not recommended. First-line management of OA comprises exercise therapy, weight loss (if overweight), education, and self-management programs to empower patients to better manage their condition. Surgical referral for knee joint replacement can be considered for patients with end-stage OA (ie, no or minimal joint space with inability to cope with pain) after using all appropriate conservative options. For patellofemoral pain, hip and knee strengthening exercises in combination with foot orthoses or patellar taping are recommended, with no indication for surgery. Conservative management (exercise therapy for 4-6 weeks) is also appropriate for most meniscal tears. For severe traumatic (eg, bucket-handle) tears, consisting of displaced meniscal tissue, surgery is likely required. For degenerative meniscal tears, exercise therapy is first-line treatment; surgery is not indicated even in the presence of mechanical symptoms (eg, locking, catching). Conclusions and Relevance Knee OA, patellofemoral pain, and meniscal tears are common causes of knee pain, can be diagnosed clinically, and can be associated with significant disability. First-line treatment for each condition consists of conservative management, with a focus on exercise, education, and self-management.
The Limitations of Medicine
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Diagnosis and Management of Asthma in Pregnancy
Authors: Kay Choong See
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
New York Heart Association Class and Kansas City Cardiomyopathy Questionnaire in Acute Heart Failure
Authors: Xiqian Huo, Boxuan Pu, Wei Wang, Yue Peng, Jingkuo Li, Lubi Lei, Lihua Zhang, Jing Li
Journal: JAMA Network Open (2023)

Sparse data exist regarding how clinician-assigned New York Heart Association (NYHA) class compares with heart failure (HF)-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) in acute HF.To compare concordance between NYHA class and KCCQ overall summary score (KCCQ-OS) in acute HF and investigate associations of changes in NYHA class and KCCQ-OS with long-term outcomes.In this cohort study, patients with HF were enrolled from 52 hospitals in China between August 2016 and May 2018. Among patients with NYHA class and KCCQ-OS at admission and 1 month, levels of each scale were categorized into 4 groups from worst to best. Mild and moderate to severe discordance were defined as NYHA class and KCCQ-OS differing by 1 level or 2 or more levels, respectively. Multivariable models evaluated associations between improvements in the 2 measures and outcomes. Analysis was conducted from January to March 2023.Changes in NYHA class and KCCQ-OS from admission to 1 month.All-cause mortality, cardiovascular death, or first HF rehospitalization.A total of 2683 patients (1709 [63.7%] male; median [IQR] age, 66 [56-75] years) were included. NYHA class II, III, and IV were presented in 374 patients (13.9%), 1179 patients (44.0%), and 1130 patients (42.1%), respectively, and the median (IQR) KCCQ-OS was 44.4 (28.3-61.9). Concordance, mild discordance, and moderate to severe discordance between admission NYHA class and KCCQ-OS occurred in 954 patients (35.6%), 1203 patients (44.8%), and 526 patients (19.6%), respectively. For KCCQ-OS, kernel density overlaps were 73.6% between NYHA II and III, 63.8% between NYHA II and IV, and 88.3% between NYHA III and IV. Most patients experienced improvements in NYHA and KCCQ-OS from admission to 1 month. After adjustment, there was no significant association between improvements in NYHA class and 4-year all-cause mortality, whereas 5 or more point improvements in KCCQ-OS were independently associated with a lower risk of 4-year mortality (hazard ratio, 0.84; 95% CI, 0.74-0.96; P = .01). NYHA class and KCCQ-OS improvements were both associated with decreased risk of 1-year composite cardiovascular death or HF rehospitalization.In this cohort study of acute HF, discordance between NYHA class and KCCQ was common, and KCCQ was more relevant to subsequent mortality than NYHA class.
Linking ABC transporters to the hallmarks of cancer
Authors: Laurent Duvivier, Louise Gerard, Adriana Diaz, Jean-Pierre Gillet
Journal: Trends in cancer (2023)

Human ATP-binding cassette (ABC) transporters are ubiquitously expressed and transport a broad range of endogenous and xenobiotic substrates across extra- and intracellular membranes. Mutations in ABC genes cause 21 monogenic diseases, and polymorphisms in these genes are associated with susceptibility to complex diseases. ABC transporters also play a major role in drug bioavailability, and they mediate multidrug resistance in cancer. At least 13 ABC transporters were shown to be involved in drug resistance in vitro. In the past decade, efforts have been made to elucidate their roles in tumor biology. Herein, we explore their involvement in tumorigenesis, focusing on the hallmarks of cells as they make their way from normalcy to neoplastic growth states.
Serrated colorectal cancer: preclinical models and molecular pathways
Authors: Aziz Aiderus, Nick Barker, Vinay Tergaonkar
Journal: Trends in cancer (2023)

Serrated lesions are histologically heterogeneous, and detection can be challenging as these lesions have subtle features that may be missed by endoscopy. Furthermore, while approximately 30% of colorectal cancers (CRCs) arise from serrated lesions, only 8-10% of invasive serrated CRCs exhibit serrated morphology at presentation, suggesting potential loss of apparent characteristics with increased malignancy. Thus, understanding the genetic basis driving serrated CRC initiation and progression is critical to improve diagnosis and identify therapeutic biomarkers and targets to guide disease management. This review discusses the preclinical models of serrated CRCs reported to date and how these systems have been used to provide mechanistic insights into tumor initiation, progression, and novel treatment targets.
An atlas of continuous adaptive evolution in endemic human viruses
Authors: Kathryn E. Kistler, Trevor Bedford
Journal: Cell Host & Microbe (2023)

Through antigenic evolution, viruses such as seasonal influenza evade recognition by neutralizing antibodies. This means that a person with antibodies well tuned to an initial infection will not be protected against the same virus years later and that vaccine-mediated protection will decay. To expand our understanding of which endemic human viruses evolve in this fashion, we assess adaptive evolution across the genome of 28 endemic viruses spanning a wide range of viral families and transmission modes. Surface proteins consistently show the highest rates of adaptation, and ten viruses in this panel are estimated to undergo antigenic evolution to selectively fix mutations that enable the escape of prior immunity. Thus, antibody evasion is not an uncommon evolutionary strategy among human viruses, and monitoring this evolution will inform future vaccine efforts. Additionally, by comparing overall amino acid substitution rates, we show that SARS-CoV-2 is accumulating protein-coding changes at substantially faster rates than endemic viruses.
Extension of the Segatella copri complex to 13 species with distinct large extrachromosomal elements and associations with host conditions
Authors: Aitor Blanco-Míguez, Eric J.C. Gálvez, Edoardo Pasolli, Francesca De Filippis, Lena Amend, Kun D. Huang, Paolo Manghi, Till-Robin Lesker, Thomas Riedel, Linda Cova, Michal Punčochář, Andrew Maltez Thomas, Mireia Valles-Colomer, Isabel Schober, Thomas C.A. Hitch, Thomas Clavel, Sarah E. Berry, Richard Davies, Jonathan Wolf, Tim D. Spector, Jörg Overmann, Adrian Tett, Danilo Ercolini, Nicola Segata, Till Strowig
Journal: Cell Host & Microbe (2023)

The Segatella copri (formerly Prevotella copri) complex (ScC) comprises taxa that are key members of the human gut microbiome. It was previously described to contain four distinct phylogenetic clades. Combining targeted isolation with large-scale metagenomic analysis, we defined 13 distinct Segatella copri-related species, expanding the ScC complex beyond four clades. Complete genome reconstruction of thirteen strains from seven species unveiled the presence of genetically diverse large circular extrachromosomal elements. These elements are consistently present in most ScC species, contributing to intra- and inter-species diversities. The nine species-level clades present in humans display striking differences in prevalence and intra-species genetic makeup across human populations. Based on a meta-analysis, we found reproducible associations between members of ScC and the male sex and positive correlations with lower visceral fat and favorable markers of cardiometabolic health. Our work uncovers genomic diversity within ScC, facilitating a better characterization of the human microbiome.
Device-measured physical activity, sedentary time, and risk of all-cause mortality: an individual participant data analysis of four prospective cohort studies
Authors: Edvard H Sagelv, Laila Arnesdatter Hopstock, Bente Morseth, Bjørge H Hansen, Jostein Steene-Johannessen, Jonas Johansson, Anna Nordström, Pedro F Saint-Maurice, Ola Løvsletten, Tom Wilsgaard, Ulf Ekelund, Jakob Tarp
Journal: British Journal of Sports Medicine (2023)

Objectives To examine whether moderate-to-vigorous physical activity (MVPA) modifies the association between sedentary time and mortality and vice versa, and estimate the joint associations of MVPA and sedentary time on mortality risk. Methods This study involved individual participant data analysis of four prospective cohort studies (Norway, Sweden, USA, baseline: 2003–2016, 11 989 participants ≥50 years, 50.5% women) with hip-accelerometry-measured physical activity and sedentary time. Associations were examined using restricted cubic splines and fractional polynomials in Cox regressions adjusted for sex, education, body mass index, smoking, alcohol, study cohort, cardiovascular disease, cancer, and/or diabetes, accelerometry wear time and age. Results 6.7% (n=805) died during follow-up (median 5.2 years, IQR 4.2 years). More than 12 daily sedentary hours (reference 8 hours) was associated with mortality risk only among those accumulating &lt;22 min of MVPA per day (HR 1.38, 95% CI 1.10 to 1.74). Higher MVPA levels were associated with lower mortality risk irrespective of sedentary time, for example, HR for 10 versus 0 daily min of MVPA was 0.85 (95% CI 0.74 to 0.96) in those accumulating &lt;10.5 daily sedentary hours and 0.65 (95% CI 0.53 to 0.79) in those accumulating ≥10.5 daily sedentary hours. Joint association analyses confirmed that higher MVPA was superior to lower sedentary time in lowering mortality risk, for example, 10 versus 0 daily min of MVPA was associated with 28–55% lower mortality risk across the sedentary time spectrum (lowest risk, 10 daily sedentary hours: HR 0.45, 95% CI 0.31 to 0.65). Conclusions Sedentary time was associated with higher mortality risk but only in individuals accumulating less than 22 min of MVPA per day. Higher MVPA levels were associated with lower mortality risk irrespective of the amount of sedentary time.
Colostomy using a percutaneous lumen-apposing metal stent
Authors: Kirill Basiliya, Jurjen J. Boonstra, Akin Inderson
Journal: Endoscopy (2023)

A 55-year-old man with a history of Crohn's disease with multiple abdominal resections, poor wound healing, and rectal cancer with pulmonary metastasis presented with abdominal distension, pain, and absence of bowel movement. A computed tomography scan showed a distended colon, with the known obstructing malignant lesion in the rectum. A surgical colostomy was judged not to be possible owing to his history of multiple and extensive abdominal surgical procedures. A colonic stent was not possible owing to the distal position and length of the lesion.
Chronic esophagotracheal fistula secondary to esophageal diverticulum successfully treated by endoscopic submucosal dissection and dual action tissue clip
Authors: Lei Shi, Fei Long, Hongwei Xu, Na Chen, Jian Ge, Ruzhen Jia, Junmei Jiang
Journal: Endoscopy (2023)

Esophagotracheal fistula secondary to esophageal diverticulum is rare but challenging to treat [1]. Some cases of esophagotracheal fistula successfully treated by endoscopic submucosal dissection (ESD) have been reported [2] [3] [4], but to our knowledge we report the first case of esophagotracheal fistula secondary to esophageal diverticulum successfully treated by ESD and clip closure.
A novel self-shaping magnetic compression anastomosis ring for treatment of colonic stenosis
Authors: Miaomiao Zhang, Shuixiang He, Huanchen Sha, Hairong Xue, Yi Lv, Xiaopeng Yan
Journal: Endoscopy (2023)

Magnetic compression anastomosis (MCA) has been used for the treatment of severe colorectal stenosis and atresia [1] [2] [3]. Herein we report a case of stenosis of the descending colon treated with transanal single-channel MCA.
Endoscopic ultrasound-guided drainage of a complex kidney abscess penetrating to the gallbladder and right liver lobe
Authors: Katarzyna M. Pawlak, Mateusz Jagielski, Eryk Bella, Kareem Khalaf, Klaus Mönkemüller, Marek Jackowski
Journal: Endoscopy (2023)

A 64-year-old woman with a past medical history of poorly controlled diabetes, morbid obesity, hypertension, and status post-oncological treatment for metastatic sigmoid colon cancer was admitted to the surgery department due to a 50 × 40 × 43-mm abscess in the right kidney on computed tomography (CT) ([Fig. 1]). The abscess penetrated the gallbladder, causing its perforation. It also penetrated the liver and was causing renal artery infiltration with pseudoaneurysm formation (21 mm and 16 mm in diameter) ([Fig. 2]). The patient was clinically and biochemically septic. CT ruled out other sites of abscess. Due to significant associated co-morbidities, poor general status, and poor percutaneous access, neither a standard surgical intervention nor percutaneous drainage was feasible.
Novel sheath device for pancreatic biopsies in intraductal papillary mucinous carcinoma with parenchymal invasion
Authors: Fumitaka Niiya, Masataka Yamawaki, Jun Noda, Tetsushi Azami, Yuichi Takano, Fumiya Nishimoto, Masatsugu Nagahama
Journal: Endoscopy (2023)

Preoperative evaluation of intraductal papillary mucinous carcinoma is challenging because "high-risk stigmata" in international guidelines are not always malignant [1]. Surgery is strongly recommended if pancreatic parenchymal invasion can be confirmed histologically [2]. Transpapillary biopsy for intraductal papillary mucinous neoplasms improves diagnostic yields [3]; nonetheless, it is difficult to diagnose parenchymal invasion on small biopsy specimens and the pancreatitis risk due to the repeated insertion of biopsy forceps into the main pancreatic duct cannot be ignored.
One-Year Outcomes After Amulet or Watchman Device for Percutaneous Left Atrial Appendage Closure: A Prespecified Analysis of the SWISS-APERO Randomized Clinical Trial
Authors: Roberto Galea, Nicolas Meneveau, Federico De Marco, Adel Aminian, Dik Heg, Konstantina Chalkou, Christoph Gräni, Frederic Anselme, Anna Franzone, Pascal Vranckx, Urs Fischer, Francesco Bedogni, Lorenz Räber, Marco Valgimigli
Journal: Circulation (2023)
Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study
Authors: Ruben A. Mesa, Claire Harrison, Jeanne M. Palmer, Vikas Gupta, Donal P. McLornan, Mary Frances McMullin, Jean-Jacques Kiladjian, Lynda Foltz, Uwe Platzbecker, Maria Laura Fox, Adam J. Mead, David M. Ross, Stephen T. Oh, Andrew Charles Perkins, Michael F. Leahy, Jun Kawashima, Sunhee Ro, Rafe Donahue, Boris Gorsh, Samineh Deheshi, Srdan Verstovsek
Journal: HemaSphere (2023)

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients’ quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.